Integrin receptors are transmembrane, non-covalently linked heterodimers consisting of one α-chain and one β-chain. In addition to performing a structural adhesive function, integrin receptors transmit extracellular signals across the plasma membrane. The integrin receptor α4β1 (also referred to as VLA-4) mediates cell adhesion by binding with either of two protein ligands: vascular cell adhesion molecule-1 (VCAM-1) (Osborn, L.; et al., Cell, 1989, 59, 1203), or the alternatively-spliced fibronectin variant containing the type III connecting segment (CS-1) (Wayner, E. A.; et al., Cell Biol., 1989, 109, 1321). In contrast to the prototypical integrin receptors α5β1, GPIIb/IIIa and αvβ3 that recognize the Arg-Gly-Asp (RGD) tripeptide sequence in their respective ligands, α4β1 binds to other primary protein sequences. The α4β1 integrin receptor recognizes Gln-Ile-Asp-Ser (QIDS) in VCAM-1 and Ile-Leu-Asp-Val (ILDV) in fibronectin. Although these sequences share a conserved Asp residue with RGD, they are otherwise unrelated. Additionally, recent studies have found that α4β1 binds the matrix ligand osteopontin (Bayless, K. J.; et al., J. Cell Sci., 1998, 111, 1165). The osteopontin ligand interaction with the α4β1 receptor may be very important as osteopontin is strongly up-regulated in inflammatory settings, including the inflamed lung.
The α4β1 integrin receptor is expressed at high levels on mast cells, mononuclear leukocytes, eosinophils, macrophages, and basophils (Adams, S. P.; et al., Ann. Rep. Med. Chem., 1999, 34, 179). The binding of α4β1 to cytokine-induced VCAM-1 on high-endothelial venules at sites of inflammation results in leukocyte/endothelium adhesion followed by extravasation into the inflamed tissue (Chuluyan, H. E.; et al., Springer Semin. Immunopathol., 1995, 16, 391). The role of mast cells and eosinophils in lung inflammation is well-established. Induction of VCAM-1 expression on airway endothelial cells seems to play a central role in lung inflammation. The α4β1 receptor interaction with VCAM-1 also exerts an important effect in stem cell adhesion to bone marrow stromal cells (Simmons, P. J.; et al., Blood, 1992, 80, 388).
The α4β7 integrin is expressed at high levels on lymphocytes and T cells. The trafficking of lymphocytes from the vasculature to normal mucosa and lymphoid tissues is mediated by adhesion of mucosal addressing cell adhesion molecule-1 (MAdCAM-1) with the integrin receptor α4β7. In an inflammatory setting, MAdCAM-1, an immunoglobulin superfamily adhesion molecule, specifically binds α4β7-expressing lymphocytes and participates in the homing of these cells to the mucosal endothelium. Cloning studies of human MAdCAM-1 have shown that the Leu-Asp-Thr-Ser-Leu (LDTSL) sequence of the CD loop is conserved. In fact, LDT-based peptides bind to α4β7 in a MAdCAM-1/RPMI-8866 cell adhesion assay with IC50 values in the 1-10 uM range (Shroff, H. N.; et al., Bioorg. Med. Chem. Lett., 1998, 8, 1601).
The extensive biology mediated by integrins in general and compelling data for the pathophysiological role of the leukocyte cell adhesion receptor α4β1 have spurred interest in the study of α4β1 antagonists in vivo. Cellular adhesion and migration mediated through the β1 integrins are critical components of cellular recruitment processes. The integrin α4β1 provides a key co-stimulatory signal supporting cell activation leading to growth factor and cytokine production and mediator release. Through recognition of the extracellular matrix, α4β1 increases the survival of activated cells by inhibiting apoptosis (Yoshikawa, H.; et al., J. Immunol., 1996, 156, 1832).
Monoclonal antibodies directed against α4β1 or VCAM-1 have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Laberge, S.; et al., Am. J. Respir. Crit. Care Med., 1995, 151, 822), rheumatoid arthritis (Barbadillo, C.; et al., Springer Semin. Immunopathol., 1995, 16, 375) and inflammatory bowel disease (Powrie, F.; et al., Ther. Immunol., 1995, 2, 115). The initial research in the low molecular weight α4β1 antagonist arena has focused on simple linear analogues of the prototype Leu-Asp-Val sequence. Phenylacetyl-Leu-Asp-Phe-D-Pro-NH2 (having an α4β1 IC50 value of 2 uM) exhibited efficacy similar to the α4 antibody PS/2 in a mouse model of oxazolone-induced contact hypersensitivity when administered at 6 mg/kg, sc (Tamraz, S.; et al., Springer Semin. Immunopathol. 1995, 16, 437). This tetrapeptide was also effective in a hyperlipidemic rabbit heterotopic heart allograft model (Molossi, S.; et al., J. Clin. Invest. 1995, 95, 2601).
Animal models of asthma have shown that the peptide antagonist BIO-1211 inhibits eosinophilia and airway hyperresponsiveness (Lin, K-C.; et al., J. Med. Chem. 1999, 42, 920). Pre-treatment of allergic sheep with a 3 mg nebulized dose of BIO-121 1 (having an α4β1 IC50 value of 1 nM; 1000-fold selective over α4β7) inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results suggest that compounds like BIO-1211 can effect broad pleiotropic activities by acting at α4β1 to achieve pronounced efficacy similar to corticosteroids.
VLA-4 antagonism may also be effective in reducing restenosis following percutaneous coronary interventions. Administration of an anti-α4 antibody attenuated smooth muscle cell migration associated with electrical injury of rabbit carotid arteries (Kling D, Fingerle J, Harlan J M, Lobb, R R and Lang, F, Mononuclear leukocytes invade rabbit arterial intima during thickening formation via CD-18 and VLA-4-dependent mechanisms and stimulate smooth muscle migration, Circ. Res., 1995, 77, 1121-1128) and was shown to reduce neointimal formation in baboon carotid arteries following endarterectomy (Lumsden A B, Chen C, Hughes J D, Kelly A B, Hanson S and Harker L, Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in non-human primates, J. Vasc. Surg., 1997, 26, 87-93). Furthermore, treatment with z anti-α4 antibody was associated with less neoadventitia formation and less lumenal narrowing 14 days after balloon injury of porcine coronary arteries (Labinez M, Hoffert C, pels K, Aggarawal S, Pepinsky R B, Leonw D, Koteliansky V, Lobb, R R and O'Brien E O, Infusion on and anti-alpha4 integrin antibody is associated with less adventitial formation after balloon injury of porcine coronary arteries, Can. J. Cardiol., 2000, 16, 187-196).
The recruitment of leukocytes, particularly monocytes to the vessel wall is a key component in the development of atherosclerotic lesions. VCAM-1 expression has been reported on endothelial cells in atherosclerotic lesions in humans (O'Brien K D, Allen M D, McDonald T O, Chait A, Harlan J M, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin C D, et al., Vascular cell adhesion molecule-1 is expressed in human atherosclerotic plaques: implications for the mode of progression of advanced atherosclerosis, J. Clin. Invest., 1993, 92, 945-951), mice (Nakahima Y, Raines E W, Plump A S, Breslow J L and Ross R, Upregulation of VCAM-1 and ICAM-1 at atherosclerotic-prone sites on the endothelium of ApoE-deficient mouse, Arterioscler. Thromb. Vasc. Biol., 1998, 18, 842-851) and rabbits (Ilyama K, Hajra L, Iiyam M, Li, H, DiChura M, Medoff B D and Cybulsky M I, Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesion and at sites predisposed to lesion formation, Circ. Res., 1999, 85, 199-207). Furthermore, a synthetic peptidomimetic of the connecting segment-1 (CS-1) which blocks α4β1 on the leukocyte demonstrated reduced leukocyte homing and lipid accumulation in the aortic sinus in both wild type mice and mice with a low density lipoprotein null mutation (LDLR −/−) maintained on a high fat diet (Shih P T, Brennan M-L, Vora D K, Territo M C, Strahl D, Elices M J, Aldons J and Berliner J A, Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet, Circ. Res., 1999, 84, 345-351). In studies using isolated carotid arteries from ApoE −/−mice (these mice develop spontaneous arterial atherosclerotic lesions with advanced lesions similar to those observed in humans), administration on blocking antibodies to VCAM-1 inhibited the majority of adhesion of monocytes or U937 cells on early atherosclerotic endothelia. In addition, a peptide which inhibits binding of α4β1 to both VCAM-1 and fibronectin was also effective in this model (Huo Y, Hafez-Moghadem A and Ley K, Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions, Circ. Res., 2000, 87, 153-159). These data support the role of a4β1 in regulating leukocyte recruitment in early and advanced atherosclerotic lesions.
Antibodies to MAdCAM-1 or integrin α4β7 inhibit lymphocyte binding to affinity-purified MAdCAM-1 or MAdCAM-1 transfectants in vitro (Hamann, A.; et al., J. Immunol. 1994, 152, 3282). The antibodies also block localization of lymphocytes to Peyer's patches. Murine MAdCAM-1 recognizes only α4β7 positive human lymphocyte cells lines and α4β7-high memory T cells. An in vivo role of α4β7 in inflammation has been suggested by increased expression of MAdCAM-1 on HEV-type vessels in the chronically inflamed pancreas of the non-obese mouse (Hanninen, A. C.; et al., J. Clin. Invest. 1993, 92, 2509). In fact, animal models underscore a significant function of α4β7 in both colitis (Fong, S.; et al., Immunol. Res. 1997, 16, 299) and lymphocytic inflammation of pancreatic islets or development of diabetes (Yang, X.; et al., Diabetes 1997, 46, 1542).
PCT application WO 98/53814 describes heterocyclic amide compounds as antagonists for VLA-4 and/or α4β7 antagonists of the formula: or a pharmaceutically acceptable salt thereof wherein R1 is alkyl, alkenyl, alkynyl, Cy, Cy-alkyl, Cy-alkenyl or Cy-alkynyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with Ra; and Cy is optionally substituted with Rb; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with Ra; and aryl and heteroaryl are optionally substituted with Rb; R3 is hydrogen, alkyl, Cy or Cy-alkyl; wherein alkyl is optionally substituted with Ra; and Cy is optionally substituted with Rb; R4 is hydrogen, alkyl, alkenyl, alkynyl, Cy, Cy-alkyl, Cy-alkenyl or Cy-alkynyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with phenyl and Rx; and Cy is optionally substituted with Ry; or, R3, R4 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteroatoms selected from N, O and S; R5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with Rx; and aryl and heteroaryl are optionally substituted with Ry; or, R4, R5 and the carbon to which they are attached together form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S; R6, R7 and R8 are each independently selected from Rd or Rx; or, two of R6, R7 and R8 and the atom to which both are attached, or two of R6, R7 and R8 and the two adjacent atoms to which they are attached together form a 5-7 membered saturated or unsaturated monocyclic ring containing 0-3 heteroatoms selected from N, O or S; Ra is Cy, or a group selected from Rx; wherein Cy is optionally substituted with Rc; Rb is a group selected from Ra, alkyl, alkenyl, alkynyl, aralkyl or heteroaralkyl; wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted with Rc; Rb is halogen, NO2, C(O)ORf, alkyl, alkoxy, aryl, aralkyl, aryloxy, heteroaryl, NRfRg, NRfC(O)Rg, NRfC(O)NRfRg, or CN; Rd and Re are independently selected from hydrogen, alkyl, alkenyl, alkynyl, Cy and Cy-alkyl; wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with Rc; or, Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5-7 members containing 0-2 additional heteroatoms independently selected from N, O and S; Rf and Rg are independently selected from hydrogen, alkyl, Cy and Cy-alkyl; wherein Cy is optionally substituted with alkyl; or, Rf and Rg together with the carbon to which they are attached form a ring of 5-7 members containing 0-2 heteroatoms independently selected from N, O and S; Rh is hydrogen, alkyl, alkenyl, alkynyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl or —SO2Ri; wherein alkyl, alkenyl and alkynyl are optionally substituted with Ra; and aryl and heteroaryl are optionally substituted with Rb; Ri is alkyl, alkenyl, alkynyl or aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with Rc; Rk is —ORd, —NO2, halogen, —S(O)mRd, —SRd, —S(O2)ORd, —S(O)mNRdRe, —NRdRe, —O(CRfRg)nNRdRe, —C(O)Rd, —CO2Rd, —CO2(C RfRg)nC(O)N RdRe, —OC(O)Rd, CN, C(O)NRdRe, —NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), —CF3, oxo, —NRdC(O)NRdSO2Ri, —NRdS(O)mRe, —OS(O2)ORd or —OP(O)(ORd)2; Ry is a group selected from Rk, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with Rx; Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; X is —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mORd, C(O)NRdRh or -5-tetrazolyl; Y is —C(O)—, —O—C(O)—, —NReC(O)—, —SO2—, —P(O)(OR4) or C(O)C(O); Z and A are independently selected from —C— and —C—C—; and, B is selected from the group consisting of a bond, —C—, —C—C—, —C═C—, a heteroatom selected from the group consisting of N, O and S; and —S(O)m—. Specific examples which exemplify some of the typical compounds disclosed have the following typical formulae: 
PCT application WO 00/43354 describes multicyclic compounds as inhibitors of leukocyte adhesion mediated by VLA-4 of the formula: wherein ring A is a multicyclic bridged cycloalkyl, multicyclic bridged cycloalkenyl or multicyclic bridged heterocyclic group provided the multicyclic bridged heterocyclic group does not contain a lactam and further wherein said multicyclic bridged cycloalkyl, multicyclic bridged cycloalkenyl or multicyclic bridged heterocyclic group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2—NR-alkyl, —NRS(O)2—NR-substituted alkyl, —NRS(O)2—NR-aryl, —NRS(O)2—NR-substituted aryl, —NRS(O)2—NR-heteroaryl, —NRS(O)2—NR-substituted heteroaryl, —NRS(O)2—NR-heterocyclic, —NRS(O)2—NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O)2—R′]2 And —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with —SO2-alkyl, —SO2-substituted alkyl, —SO2-alkenyl, —SO2-substituted alkenyl, —SO2-cycloalkyl, —SO2-substituted cycloalkyl, —SO2-aryl, —SO2-substituted aryl, —SO2-heteroaryl, —SO2-substituted heteroaryl, —SO2-heterocyclic, —SO2-substituted heterocyclic and —SO2NRR where R is hydrogen or alkyl; R1 is selected from the group consisting of: (a) —(CH2)x—Ar—R5 where R5 is selected from the group consisting of —O—Z—NR6R6′ and —O—Z—R7 wherein R6 and R6′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R6 and R6′ are joined to form a heterocycle or a substituted heterocycle, R7 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)—and —SO2—, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; (b) Ar1—Ar2—C1-10alkyl—, Ar1—Ar2—C2-10alkenyl—, Ar1—Ar2—C2-10alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; (c) —(CH2)x—Ar—R8, wherein R8 is heterocyclic or substituted heterocyclic; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; (d) —(CH2)x—Ar—R9, wherein R9 is —C1-10alkyl, —C2-10alkenyl or —C2-10alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; (e) —(CH2)x—Cy—, wherein Cy is optionally substituted with 1 to 4 substituents selected from R2 is selected from the group consisting of hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; R3 is selected from the group consisting of hydrogen, C1-10alkyl optionally substituted with one to four substituents independently selected from Ra and Cy optionally substituted with one to four substituents independently selected from Rb; Ra is selected from the group consisting of Cy, —ORd, —NO2, halogen, —S(O)mRd, —SRd, —S(O)2ORd, —S(O)mNRdRe, NRdRe, —O(CNRfRg)nNRdRe, —C(O)Rd, —CO2Rd, —CO2(CRfRg)nCONRdRe, —OC(O)Rd, —CN, C(O)NRdRe, NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), CF3, and —OCF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc; Rb is selected from the group consisting of Ra, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl C1-10alkyl, heteroaryl, C1-10alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc; Rc is selected from the group consisting of halogen, amino, carboxy, C1-4alkyl, C1-4alkoxy, aryl, aryl C1-4alkyl, hydroxy, CF3, and aryloxy; Rd and Re are independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, Cy and Cy—C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and Rg are independently selected from hydrogen, C1-10alkyl, Cy and Cy—C1-10alkyl; or Ra Rf and Ra R9 together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Rh is selected from the group consisting of hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, cyano, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10alkyl, or —SO2Ri; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb; Ri is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X1 is selected from the group consisting of —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mORd, —C(O)NRdRh, and -5-tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and pharmaceutically acceptable salts thereof. Preferred compounds of this invention are represented by formula II: wherein R1, R2 and R3 are as defined above; Y is selected from the group consisting of hydrogen, Rd, Cy, —ORd, —NO2, halogen, —S(O)mRd, —SRd, —S(O)2ORd, —S(O)mNRdRe, —NRdRe, —O(CRfRg)nNRdRe, —C(O)Rd,—CH(OH)Rd, —CO2Rd, —CO2(CRfRg)nCONRdRe, —OC(O)Rd, —CN, C(O)NRdRe, NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), CF3, and —OCF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc; where Cy, Rc, Rd, Re, Rf, Rg, Rh, m and n are as defined herein; R4 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyllieteroaryl, carboxyl-substituted heteroaryl, carboxyllieterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiolheteroaryl, substituted thiolheteroaryl, thiolheterocyclic, substituted thiolheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2-NRR where each R is independently hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2—NR-alkyl, —NRS(O)2—NR-substituted alkyl, —NRS(O)2—NR-aryl, —NRS(O)2—NR-substituted aryl, —NRS(O)2—NR-heteroaryl, —NRS(O)2—NR-substituted heteroaryl, —NRS(O)2—NR-heterocyclic, —NRS(O)2—NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O)2—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with —SO2-alkyl, —SO2-substituted alkyl, —SO2-alkenyl, —SO2-substituted alkenyl, —SO2-cycloalkyl, —SO2-substituted cycloalkyl, —SO2-aryl, —SO2-substituted aryl, —SO2-heteroaryl, —SO2-substituted heteroaryl, —SO2-heterocyclic, —SO2-substituted heterocyclic and —SO2NRR where R is hydrogen or alkyl; or Rb where Rb is as defined above; X2 is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; or Rd where Rd is as defined above; v is an integer ranging from 0 to 3; and pharmaceutically acceptable salts thereof.
The structural topology represented by the formulae described in these references differs significantly from that represented by the compounds of the present invention.
Accordingly, it is an object of the present invention to provide aza-bridged-bicyclic compounds that are α4 integrin receptor antagonists; more particularly, the α4β1 and the α4β7 integrin receptor. It is also an object of the present invention to provide a process for preparing derivatives of aza-bridged-bicyclic amino acid compounds, compositions, intermediates and derivatives thereof. It is a further object of the invention to provide methods for the treatment of integrin mediated disorders that are ameliorated by inhibition of the α4β1 and α4β7 integrin receptor including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.